Genetic Analysis of Inherited Hypertension in the Rat

Blood pressure is a quantitative trait that has a strong genetic component in humans and rats. Several selectively bred strains of rats with divergent blood pressures serve as an animal model for genetic dissection of the causes of inherited hypertension. The goal is to identify the genetic loci controlling blood pressure, i.e., the so-called quantitative trait loci (QTL). The theoretical basis for such genetic dissection and recent progress in understanding genetic hypertension are reviewed. The usual paradigm is to produce segregating populations derived from a hypertensive and normotensive strain and to seek linkage of blood pressure to genetic markers using recently developed statistical techniques for QTL analysis. This has yielded candidate QTL regions on almost every rat chromosome, and also some interactions between QTL have been defined. These statistically defined QTL regions are much too large to practice positional cloning to identify the genes involved. Most investigators are, therefore, fine mapping the QTL using congenic strains to substitute small segments of chromosome from one strain into another. Although impressive progress has been made, this process is slow due to the extensive breeding that is required. At this point, no blood pressure QTL have met stringent criteria for identification, but this should be an attainable goal given the recently developed genomic resources for the rat. Similar experiments are ongoing to look for genes that influence cardiac hypertrophy, stroke, and renal failure and that are independent of the genes for hypertension.